2012 Grants - Hegde

Oxidized Amyloid Proteins Induce Genome Damage in Alzheimer's Disease

2012 New Investigator Research Grant

The brains of people with Alzheimer's disease are characterized by certain protein accumulations, including plaques that contain beta-amyloid and neurofibrillary tangles that contain tau. Alzheimer's brains also harbor accumulated iron and copper ions (or electrically charged iron and copper particles). These concentrated proteins and metals tend to induce the overproduction of toxic oxygen molecules in the brain, which can cause damage known as oxidative stress in nerve cells. Oxidative stress may hasten a process called apoptosis, or programmed cell death. In healthy brains, apoptosis is used to destroy sick or unwanted cells. But the process becomes abnormally activated in Alzheimer's, causing the death of healthy neurons.

Muralidhar L. Hegde, Ph.D., and colleagues have been searching for mechanisms that may explain the toxicity of accumulated proteins and metals in the brain. In preliminary experiments, they created brain cell cultures in which the cells were exposed to dementia-related proteins (beta-amyloid, tau and alpha-synuclein) as well as iron and copper ions. They found that this exposure caused damage to the structure of the cells' DNA. To explain their finding, Dr. Hegde and colleagues argued that the metal ions likely induced the production of toxic oxygen molecules in the beta-amyloid, tau and alpha-synuclein. Then, when these "toxified" proteins bound to the cultured cells' DNA, they likely induced the DNA damage. Dr. Hegde's team further argued that such damage might trigger apoptosis in the cells.

For their proposed grant, the researchers will use more extensive tests with laboratory cells to prove their study's hypotheses. Specifically, they hope to determine exactly where beta-amyloid, tau and alpha-synuclein bind to brain cell DNA. They also hope to characterize more accurately the DNA damage caused by such binding. In addition, the team will experiment with compounds that can ameliorate the process of oxidative stress induced by protein/metal interactions. If such compounds can prevent the proteins from damaging cellular DNA, they may provide the basis for novel Alzheimer's treatments.